Cholesterol that is absorbed from the intestinal contents contributes significantly to the plasma levels of non-HDL cholesterol. Since non-HDL cholesterol is a positive risk factor for the progression of atherosclerosis and coronary artery disease (CAD), methods to inhibit intestinal cholesterol absorption have clinical potential for the treatment of hypercholesterolemic patients at risk for CAD.
Phosphatidylcholine (hereinafter "PC"), which enters the intestinal lumen from the bile and the diet, is considered to participate in cholesterol absorption by enhancing the solubility of cholesterol in bile acid micelies. It has been reported, however, that biliary PC also retards intestinal cholesterol absorption. This diametric effect of PC on cholesterol absorption was confirmed in later in vitro studies with isolated rat intestinal segments (Rampone A. J. and Machida C. M., "Mode of action of lecithin in suppressing cholesterol absorption." J. Lipid Res., 22:744-752 (1981)), and in intestinal perfusion studies (Hollander D., and Morgan D., "Effect of plant sterols fatty acids and , lecithin on cholesterol absorption in vivo in the rat." Lipids, 15:395-400 (1980)). Similar suppression of cholesterol absorption by PC has been demonstrated in vivo in human subjects (Beil F. U. and Grundy S. M., "Studies on plasma lipoproteins during absorption of exogenous lecithin in man" J. Lipid Res., 21:525-536 (1980)).
Lumenal PC is hydrolyzed to lysophosphatidylcholine and free fatty acid by pancreatic phospholipase A.sub.2. When the effect of lysophosphatidylcholine on cholesterol absorption by intestinal segments was examined no inhibition was observed indicating that intact PC is required to suppress cholesterol absorption (Rampone A. J. and Long L. R., "The effect of phosphatidylcholine and lysophosphatidylcholine on the absorption and mucosal metabolism of oleic acid and cholesterol in vitro." Biochim. Biophys. Acta, 486:500-510 (1977)).
The foregoing conclusion that PC in the intestinal contents blocks intestinal lipid absorption is supported by studies in which cholesterol absorption was significantly inhibited in rats fed a cholesterol-loaded lipid emulsion containing nondigestible diether PC analogs (O'Connor P. J., Loiudice T. A., Bochenek W., and Rodgers J. B., "Effect of diester and diether phosphatidylcholine on intestinal absorption of neutral and acidic sterois." Digestive Diseases, 23:316-320 (1978)).
Collectively, these published observations point to the hydrolysis of PC by pancreatic phospholipase A.sub.2 as the critical step in the initiation of intestinal cholesterol absorption. The dependence of cholesterol absorption on phospholipase A.sub.2 activity can be the basis for pharmacological treatment of hyperlipidemic persons with nonabsorbable pancreatic phospholipase A.sub.2 inhibitors.